Normal adult hemoglobin comprises a molecule with four polypeptide chains, two of which are designated .alpha. subunits and two of which are designated .beta. subunits. Diseases known as sickle cell syndromes are associated with disorders in the .beta. chain of the hemoglobin. However, in mammals, and particularly in humans, during fetal development, the fetus produces a fetal hemoglobin which comprises, instead of .beta.-globin proteins, two .gamma.-globin proteins. At some point during fetal development or infancy, depending on the particular species and individual, there is a so-called "globin switch" whereby the precursors of erythrocytes in the fetus switch from making predominantly .gamma.-globin to making predominantly .beta.-globin. It has been observed, however, that increased levels of fetal hemoglobin (derived from .gamma.-globin) ameliorate the severity of sickling disorders. It has also been observed that subjects heterozygous for hereditary persistence of fetal hemoglobin syndromes (HPFH) and sickling hemoglobin (HbS) are clinically asymptomatic of sickle cell anemia. Also, infants with sickle cell anemia do not usually develop the symptoms of the disease until approximately four months of age when their fetal hemoglobin levels decrease. These observations suggest that a method for increasing the levels of fetal hemoglobin would be beneficial to patients with sickle cell syndromes.
It is thus an object of the present invention to provide a method for inhibiting or reversing the .gamma. to .beta.-globin switch in a fetus or infant to maintain increased fetal hemoglobin levels in those individuals with sickle cell syndromes and .beta.-thalassemias.
Inhibin is a hormone which, among other effects, suppresses secretion of FSH (follicle-stimulating hormone) from the pituitary gland. Inhibin is a protein consisting of .alpha. and .beta..sub.A subunits linked by disulfide bonds. Activin, another hormone, sometimes also referred to as erythroid differentiation factor (EDF) or follicle-stimulating hormone releasing protein (FRP), is a homodimer consisting of either two .beta..sub.A subunits of inhibin (Activin A), two .beta..sub.B subunits of inhibin (Activin B), or a subunit each of .beta..sub.A and .beta..sub.B (Activin AB). These materials are present, in analogous forms, in mammals and have been reported, for instance, in human, porcine, and bovine follicular fluid. Porcine inhibin has been purified and sequenced from porcine follicular fluid as described in U.S. Pat. No. 4,740,587. The DNA encoding the prepro inhibin .alpha. and .beta. chains of porcine or human inhibin has been isolated, ligated into expression vectors and expressed in mammalian culture See European Patent Application No. 222,491, published May 20, 1987. Activin A has been shown to induce hemoglobin accumulation in a human erythroleukaemic cell line and to induce the proliferation of erythroid progenitor cells in human bone marrow culture See Yu, et al., Nature, 330, 765 (Dec. 24, 1987). The structures and isolation of activin have been reported by several groups in the literature. See Vale, et al., Nature, 321: 776 (1986): Ling, et al., Nature, 321: 779 (1986); Ito, et al., Biochem. Biophys. Res. Comm., 142, 1095 (1987); Tsuji, et al., Biotech. Bioeno., 31, 675 (1988); Shibata, et al., Biochem. Biophys. Res. Comm., 146. 187 (1987). It has unexpectedly been found by the inventors herein that both activin and inhibin may inhibit or even reverse the .gamma. to .beta.-globin switch in a fetus or mammalian infant.
It is thus another object of the present invention to provide an agent for maintaining a high level of chain synthesis (thereby maintaining high fetal hemoglobin levels), without significant toxicity and long term side effects.